The invention relates to, as novel and useful industrial products, biphenyl derivatives substituted with an aromatic or heteroaromatic radical. The invention also relates to the use of these novel compounds in pharmaceutical compositions intended for use in human or veterinary medicine, or alternatively in cosmetic compositions.
The compounds according to the invention have pronounced activity in the fields of cell differentiation and proliferation and find applications more particularly in the topical and systemic treatment of dermatological complaints associated with a keratinization disorder, dermatological (or other) complaints with an inflammatory and/or immunoallergic component, and dermal or epidermal proliferations, whether they are benign or malignant. These compounds can also be used in the treatment of connective tissue degenerative diseases, for controlling ageing of the skin, whether this is light-induced or chronological ageing, and for treating cicatrization disorders. They moreover find an application in the opthalmological field, in particular in the treatment of corneopathy.
The compounds according to the invention can also be used in cosmetic compositions for body and hair hygiene.
Triaromatic derivatives whose structure consists essentially of two substituted aromatic rings linked together by a 5- or 6-membered heteroaryl divalent radical containing, as hetero atom, an oxygen atom, a sulphur atom and/or at least one nitrogen atom, have already been described in EP-382,077.
The compounds according to the present invention, which are also triaromatic derivatives, differ from those of EP-382,077 essentially in that if they have a heteroaryl radical, in particular a substituted pyridyl, furyl or thienyl radical, this radical is located at the end of the chain, thus giving these compounds a chemical structure which is totally different from that of the compounds of EP-382,077.
Although the compounds according to the invention are not limited to those containing a heteroaryl radical, it has nevertheless been found, surprisingly and unexpectedly, that the compounds containing such a radical have excellent pharmaceutical and cosmetic properties which are entirely similar to those of the compounds according to the invention containing a substituted phenyl radical at the end of the chain.
It has moreover been possible to demonstrate that the compounds according to the invention are devoid of side effects, while at the same time having excellent activity.
The subject of the present invention is thus novel compounds which can be represented by the following general formula: 
in which:
Ar represents an aromatic or heteroaromatic radical chosen from: 
Z being O or S,
R1 represents xe2x80x94CH3, xe2x80x94CH2xe2x80x94OH, xe2x80x94OR8 or xe2x80x94COR9,
R2 and R3, which may be identical or different, represent H, linear or branched C1-C15 alkyl, cycloalkyl, xe2x80x94ZR10 or a polyether radical, at least one from among R2 and R3 representing a linear or branched C1-C15 alkyl, or
R2 and R3, taken together, form a 5- or 6-membered ring, optionally substituted with at least one methyl and/or optionally interrupted by an oxygen or sulphur atom or by an SO or SO2 radical,
R4 represents H, a halogen atom, linear or branched C1-C20 alkyl, xe2x80x94OR10, xe2x80x94OCOR11 or a polyether radical,
R5 represents H, a halogen atom, linear or branched C1-C20 alkyl, xe2x80x94OCOR11, xe2x80x94OR12, mono- or polyhydroxyalkyl, xe2x80x94NO2, 
xe2x80x83xe2x80x94(CH2)nxe2x80x94NHCOCH3, xe2x80x94CHxe2x95x90CHxe2x80x94COR13, xe2x80x94(CH2)nCOR13, n being 0 to 6, xe2x80x94Oxe2x80x94(CH2)mCOR13, xe2x80x94Oxe2x80x94(CH2)mOH, m being 1 to 12, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, a polyether radical or a xe2x80x94CH2-polyether radical,
R6 represents H, lower alkyl or xe2x80x94OR10,
R7 represents H, a halogen atom, linear or branched C1-C20 alkyl, xe2x80x94OR10 or xe2x80x94OCOR11 or a polyether radical,
R8 represents H, lower alkyl or xe2x80x94COR11,
R9 represents H, lower alkyl, xe2x80x94OR14 or 
R10 represents H or lower alkyl,
R11 represents lower alkyl,
R12 represents H, linear or branched C1-C20 alkyl, mono- or polyhydroxyalkyl, or optionally substituted aryl or aralkyl,
R13 represents H, lower alkyl, xe2x80x94OR10, aryl or 
R14 represents H, alkyl, linear or branched C1-C20 alkyl, alkenyl, mono- or polyhydroxyalkyl, optionally substituted aryl or aralkyl, or a sugar residue,
rxe2x80x2 and rxe2x80x3, which may be identical or different, represent H, OH, lower alkyl, mono- or poly-hydroxyalkyl, optionally substituted aryl, an amino acid residue or a peptide residue, or rxe2x80x2 and rxe2x80x3, taken together, form a heterocycle,
and the salts of the compounds of formula (I) when R1 represents a carboxylic acid function, as well as the optical and, geometrical isomers of the said compounds of formula (I).
When the compounds according to the invention are in the form of a salt, this is preferably a salt of an alkali metal or alkaline-earth metal, or alternatively of zinc or of an organic amine.
According to the present invention, the expression xe2x80x9clower alkylxe2x80x9d refers to a C1-C6 radical, preferably the methyl, ethyl, isopropyl, butyl, tert-butyl and hexyl radicals.
The term xe2x80x9clinear or branched C1-C15 alkylxe2x80x9d refers in particular to the methyl, ethyl, propyl, 2-ethylhexyl, octyl and dodecyl radicals. When the alkyl radical is C1-C20, the hexadecyl and octadecyl radicals are also intended.
The term xe2x80x9ccycloalkylxe2x80x9d refers to an optionally substituted mono- or polycyclic radical containing from 5 to 10 carbon atoms, in particular a cyclopentyl, cyclohexyl, 1-methylcyclohexyl or 1-adamantyl radical.
The term xe2x80x9cmonohydroxyalkylxe2x80x9d refers to a radical preferably containing 1 to 6 carbon atoms, in particular a hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl radical.
The term xe2x80x9cpolyhydroxyalkylxe2x80x9d refers to a radical preferably containing 3 to 6 carbon atoms and from 2 to 5 hydroxyl groups, such as the 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl and 2,3,4,5-tetrahydroxypentyl radicals or a pentaerythritol residue.
The term xe2x80x9cpolyether radicalxe2x80x9d refers to a radical containing from 2 to 6 carbon atoms which is interrupted by at least two oxygen atoms, such as the methoxymethoxy, methoxyethoxy and methoxyethoxymethoxy radicals.
The term xe2x80x9cxe2x80x94CH2-polyether radicalxe2x80x9d refers to a radical preferably chosen from the methoxymethoxymethyl, ethoxymethoxymethyl and methoxyethoxymethoxymethyl radicals.
The term xe2x80x9carylxe2x80x9d preferably refers to a phenyl radical optionally substituted with at least one halogen, a lower alkyl, a hydroxyl, a C1-C3 alkoxy, a nitro function, a polyether radical or an amino function optionally protected with an acetyl group or optionally substituted with at least one C1-C6 lower alkyl or alkoxy.
The term xe2x80x9caralkylxe2x80x9d preferably refers to a benzyl or phenethyl radical optionally substituted with at least one halogen, a lower alkyl, a hydroxyl, a C1-C3 alkoxy, a nitro function, a polyether radical or an amino function optionally protected with an acetyl group or optionally substituted with at least one C1-C6 lower alkyl or alkoxy.
The term xe2x80x9cheteroaryl radicalxe2x80x9d preferably refers to a pyridyl, furyl or thienyl radical, optionally substituted with at least one halogen, a lower alkyl, a hydroxyl, a C1-C3 alkoxy, a nitro function, a polyether radical or an amino function optionally protected with an acetyl group or optionally substituted with at least one C1-C6 lower alkyl or alkoxy.
The term xe2x80x9calkenylxe2x80x9d refers to a radical preferably containing 2 to 5 carbon atoms and containing one or more ethylenic unsaturations, such as, more particularly, an allyl radical.
The term xe2x80x9csugar residuexe2x80x9d refers to a residue derived in particular from glucose, from galactose or from mannose, or alternatively from glucuronic acid.
The term xe2x80x9camino acid residuexe2x80x9d refers in particular to a residue derived from lysine, from glycine or from aspartic acid, and the term xe2x80x9cpeptide residuexe2x80x9d refers more particularly to a dipeptide or tripeptide residue resulting from the combination of amino acids.
The term xe2x80x9cheterocyclexe2x80x9d preferably refers to a piperidino, morpholino, pyrrolidono or piperazino radical, optionally substituted in position 4 with a C1-C6 lower alkyl or a mono- or polyhydroxyalkyl as defined above.
When R4, R5 and/or R7 represent a halogen atom, this is preferably a fluorine, chlorine or bromine atom.
According to a preferred embodiment, the compounds according to the invention correspond to the general formulae (II) and (III) below: 
in which:
Ar represents a radical of formula (a) or (b) below: 
R1, R4, R5, R6, R7 and Z having the same meanings as those given above for formula (I),
R15, R16, R17 and R18, which may be identical or different, represent H or xe2x80x94CH3, and
t is 1 or 2.
Among the compounds of formulae (I) to (III) above, according to the present invention, mention may be made in particular of the following:
4-[4-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenyl]benzoic acid, and its methyl ester,
4-[4-(5-hydroxypentyloxy)-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenyl]benzoic acid, and its methyl ester,
4-[4-(6-hydroxyhexyloxy)-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenyl]benzoic acid and its methyl ester,
4-[4-(7-hydroxyheptyloxy)-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenyl]benzoic acid,
4-[4-(8-hydroxyoctyloxy)-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenyl]benzoic acid,
4-[4-(9-hydroxynonyloxy)-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenyl]benzoic acid,
4-[4-methoxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenyl]benzoic acid,
4-[4-methoxyethoxymethoxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenyl]benzoic acid,
4-[4-benzyloxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)phenyl]benzoic acid,
4xe2x80x2-(2,3-dihydroxypropoxy)-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid (racemic),
4xe2x80x2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-biphenyl-4-carboxylic acid (racemic),
4xe2x80x2-(2-morpholin-4-yl-ethoxy)-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
methyl 2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylate,
2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
4-methoxymethoxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
4-hydroxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
4-methoxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
3-methoxymethoxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
3-hydroxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
3-methoxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2-methoxymethoxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2-hydroxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2-methoxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x2-methoxymethoxy-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
2xe2x80x2-methoxy-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
2xe2x80x2-propyloxy-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
2xe2x80x2-hydroxy-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
4xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;2xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x2-carboxylic acid,
2xe2x80x2-methoxymethoxy-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
2xe2x80x2-hydroxy-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
2xe2x80x2-methoxy-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
3xe2x80x2-methoxymethoxymethyl-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
3xe2x80x2-hydroxymethyl-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
2xe2x80x2-(4,4-dimethylthiochroman-7-yl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x2-(4,4-dimethylthiochroman-6-yl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x2-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x2-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x2-carboxylic acid,
2xe2x80x2-(3-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x2-carboxylic acid,
2xe2x80x2-(3-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
3xe2x80x3-methyl-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x2-carboxylic acid,
2xe2x80x3-hydroxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x3-methoxymethoxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x3-methoxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x3-propyloxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
3xe2x80x3-hydroxy-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
6-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-yl]nicotinic acid,
5-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-yl]-2-pyridinecarboxylic acid,
2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-hydroxamic acid,
2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-ol,
[2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-yl]methanol,
2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carbaldehyde,
4xe2x80x2-methoxycarbonylmethoxy-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
4xe2x80x2-carboxymethoxy-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
4xe2x80x2-(5-ethoxycarbonylpentyloxy)-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
4xe2x80x2-(5-carboxypentyloxy)-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxamide,
N-ethyl-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxamide,
N,N-diethyl-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxamide,
morpholin-4-yl-[2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-yl]methanone,
(4-hydroxyphenyl)-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxamide,
3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxymethyl-4xe2x80x2-carboxylic acid,
3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4,4xe2x80x2-dicarboxylic acid,
3xe2x80x2-methoxymethoxy-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
3xe2x80x2-methoxy-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
3xe2x80x2-propyloxy-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
3xe2x80x2-hydroxy-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
4xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;3xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
4xe2x80x2-(5-carboxamidopentyloxy)-3xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
3xe2x80x2-methoxycarbonyl-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
3xe2x80x2-carboxyl-5xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-carboxylic acid,
2xe2x80x2-(4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x2-(4-methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x2-(4-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2xe2x80x2-(4-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-[1,1xe2x80x2;4xe2x80x2,1xe2x80x3]terphenyl-4xe2x80x3-carboxylic acid,
2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)biphenyl-4-yl]-4-thiophenecarboxylic acid.
A subject of the present invention is also the processes for preparing the compounds of formula (I) above according to the reaction schemes given in Tables A and B.
With reference to Table A, the compounds of formula (Ia) can be obtained by a Suzuki-type coupling reaction between a boronic derivative of formula (6) and a biaromatic bromo derivative of formula (7). The boronic derivative of formula (6) is obtained from the halo derivative of formula (5), preferably the bromo or iodo derivative. The biaromatic bromo derivative of formula (7) can be obtained by two different routes involving a Suzuki-type coupling reaction. The first consists in reacting a haloaromatic compound of formula (1) with a bromoboronic derivative of formula (2) and the second consists in reacting an aromatic boronic derivative of formula (3) with an idobromoaromatic derivative of formula (4).
The reaction conditions for these various steps are essentially described in:
N. Miyaura, Synthetic Communications 1981, 11(7), 513-9,
A. Suzuki, Synlett 1990, 221,
A. R. Martin, Acta Chemica Scandinavia 1993, 47, 221-30,
G. Marck, Tetrahedron Letters 1994, vol. 35, No. 20, 3277-80,
T. Wallow, J. Org. Chem. 1994, 59, 5034-7,
H. Zhang, Tetrahedron Letters 1996, vol. 37, No. 7, 1043-4.
The boronic derivatives of formulae (2), (3) and (6) can be prepared according to the following two methods:
(a) either by reaction with butyllithium and then with an alkyl borate, preferably triisopropyl borate or trimethyl borate, followed by hydrolysis with hydrochloric acid,
(b) or by reaction with the pinacol ester of the diboronic acid according to the method described by T. Ishiyama, J. Org. Chem. 1995, 60, 7508-10.
Starting with the compound of formula (Ia), it is possible to gain access to the compounds of formulae (Ib) and (Ic).
The compounds of formula (Ib) can be obtained from the compounds of formula (Ia) (R5=OH) by reaction of a halo derivative (9) in the presence of a solvent such as acetone, methyl ketone [sic] or DMF and a base such as potassium carbonate or sodium hydride.
The compounds of formula (Ic) can be obtained from the compounds of formula (Ia) (R5=OH) by standard acylation reaction starting with an acid (10).
The compounds of formula (Id) can be obtained from compounds of formula (Ia) (R5=OH) which are converted, in a first step, into triflate derivatives of formula (8) and then, in a second step, are reacted either under Suzuki-type reaction conditions with an aromatic boronic derivative (12), or under Stille-type reaction conditions with an aromatic stannic derivative (11) according to the method described by A. M. Echavarren, J. Am. Chem. Soc. 1987, 109, 5478-86.
Referring now to Table B, the compounds of formulae (Ie), (If) and (Ig) can be obtained directly from triflate derivatives of formula (8) by carbonylation in the presence of a palladium catalyst and using, respectively, an alcoholic derivative, an amine or a trialkylsilane, according to the methods described by J. K. Stille, Angew Chem. Int., Ed. Engl. 1996, 508-524 and H. Kotsuki, Synthesis 1996, 470-2.
The compounds of formula (Ih) can also be obtained from triflate derivatives of formula (8) by reaction with an acrylic ester (13) in the presence of a palladium catalyst, according to the method described in J. Med. Chem. 1990, vol. 33, No. 7, 1919-24. Starting with the unsaturated compound of formula (Ih), it is possible to gain access directly, by catalytic hydrogenation, to the compound of formula (Ii).
The compounds of formula (Ij) can again be obtained from triflate derivatives of formula (8) by reaction with stannic derivatives such as vinyltributyltin or allyltributyltin (14) in the presence of a palladium catalyst. The intermediate compound obtained of formula (15) is then subjected to an oxidation reaction with osmium tetroxide, under the conditions described in J. Org. Chem. 1990, vol. 55, No. 3, 906-9 and J. Med. Chem. 1991, vol. 34, No. 5, 1614-23.
When, in the compounds of formula (I) according to the invention, R1 represents a xe2x80x94COOH radical, these are prepared according to two different synthetic routes:
(a) The first consists in protecting the carboxylic acid function with a protecting group of alkyl, allyl, benzyl or tert-butyl type.
When the protecting group is an alkyl, the deprotection is obtained using sodium hydroxide or lithium hydroxide in an alcoholic solvent such as methanol, or THF.
When the protecting group is an allyl radical, the deprotection is carried out using a catalyst such as certain transition metal complexes, in the presence of a secondary amine such as morpholine.
When the protecting group is a benzyl radical, the deprotection is carried out in the presence of hydrogen using a catalyst such as palladium on charcoal.
Lastly, when the protecting group is a tert-butyl radical, the deprotection is carried out using trimethylsilane [sic] iodide.
(b) The second consists in starting with the corresponding phenolic compound, which is converted into the triflate, and is then subjected to a carbonylation in the presence of a palladium catalyst.
When, in the compounds of formula (I) according to the invention, R1 represents an alcohol function, these can be obtained:
(a) either from the corresponding aldehyde derivatives by the action of an alkali metal hydride such as sodium borohydride, in an alcoholic solvent such as methanol,
(b) or starting with the acid derivatives of formula (Ie) (R10=H) by reduction with lithium aluminium hydride.
When, in the compounds of formula (I) according to the invention, R1 represents an aldehyde function, these can be obtained by oxidation of the corresponding alcohols in the presence of manganese oxide, pyridinium dichromate or the Swern reagent.
Lastly, when, in the compounds of formula (I) according to the invention, R1 represents an amide function, these can be obtained by reaction of the acid chlorides, obtained from the corresponding carboxylic acids, with aliphatic, aromatic or heterocyclic amines in the presence of dicyclohexylcarbodiimide or carbonyldiimidazole.
A subject of the present invention is also the compounds of formula (I) as defined above, as medicinal products.
These compounds have agonist or antagonist activity with respect to the expression of one or more biological markers in the test of differentiation of mouse embryonic teratocarcinoma cells (F9) (Skin Pharmacol. 3, p. 256-267, 1990) and/or on the in vitro differentiation of human keratinocytes (Skin Pharmacol. 3, p. 70-85, 1990). These abovementioned tests show the activities of the compounds in the fields of differentiation and proliferation. The activities can also be measured in cellular transactivation tests using RAR recombinant receptors according to the method by B. A. Bernard et al., Biochemical and Biophysical Research Communication, 1992, vol. 186, 977-983.
The compounds according to the invention are particularly suitable in the following fields of treatment:
1) for treating dermatological complaints associated with a keratinization disorder which has a bearing on differentiation and on proliferation, in particular for treating common acne, comedones, polymorphonuclear leukocytes, rosacea, nodulocystic acne, acne conglobata, senile acne and secondary acne such as solar, medication-related or occupational acne,
2) for treating other types of keratinization disorder, in particular ichthyosis, ichthyosiform states, Darier""s disease, palmoplantar keratoderma, leucoplasias and leucoplasiform states, and cutaneous or mucous (buccal) lichen,
3) for treating other dermatological complaints associated with a keratinization disorder with an inflammatory and/or immunoallergic component and, in particular, all forms of psoriasis, whether it is cutaneous, mucous or ungual psoriasis and even psoriatic rheumatism, or alternatively cutaneous atopy, such as eczema or respiratory atopy or alternatively gingival hypertrophy; the compounds can also be used in certain inflammatory complaints which have no keratinization disorder;
4) for treating all dermal or epidermal proliferations, whether benign or malignant and whether they are of viral origin or otherwise, such as common warts, flat warts and verruciform epidermodysplasia, it being also possible for the oral or florid papillomatoses and the proliferations to be induced by ultraviolet radiation, in particular in the case of basocellular and spinocellular epithelioma,
5) for treating other dermatological disorders such as bullosis and collagen diseases,
6) for treating certain ophthalmological disorders, in particular corneopathies,
7) for repairing or combating ageing of the skin, whether this is light-induced or chronological ageing, or for reducing actinic keratoses and pigmentations, or any pathologies associated with chronological or actinic ageing,
8) for preventing or curing the stigmata of epidermal and/or dermal atrophy induced by local or systemic corticosteroids, or any other form of cutaneous atrophy,
9) for preventing or treating cicatrization disorders or for preventing or repairing stretch marks,
10) for combating disorders of sebaceous functioning such as the hyperseborrhoea of acne or simple seborrhoea,
11) in the treatment or prevention of cancerous or precancerous states,
12) in the treatment of inflammatory complaints such as arthritis,
13) in the treatment of any general or skin complaint of viral origin,
14) in the prevention or treatment of alopecia,
15) in the treatment of dermatological or general complaints having an immunological component,
16) in the treatment of complaints of the cardiovascular system such as arteriosclerosis.
In the therapeutic fields mentioned above, the compounds according to the invention may be employed advantageously in combination with other compounds of retinoid-type activity, with D vitamins or derivatives thereof, with corticosteroids, with anti-free-radical agents, xcex1-hydroxy or xcex1-keto acids or derivatives thereof, or alternatively with ion-channel blockers. The expression xe2x80x9cD vitamins or derivatives thereofxe2x80x9d means, for example, vitamin D2 or D3 derivatives and in particular 1,25-dihydroxyvitamin D3. The expression xe2x80x9canti-free-radical agentsxe2x80x9d means, for example, xcex1-tocopherol, superoxide dismutase or SOD, ubiquinol or certain metal-chelating agents. The expression xe2x80x9cxcex1-hydroxy or xcex1-keto acids or derivatives thereofxe2x80x9d means, for example, lactic, malic, citric, glycolic, mandelic, tartaric, glyceric or ascorbic acid or the salts, amides or esters thereof. Lastly, the term xe2x80x9cion-channel blockersxe2x80x9d means, for example, Minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) and derivatives thereof.
A subject of the present invention is also pharmaceutical compositions containing at least one compound of formula (I) as defined above, one of the optical or geometrical isomers thereof or one of the salts thereof.
The pharmaceutical compositions intended in particular for treating the abovementioned complaints, and are characterized in that they comprise a pharmaceutically acceptable support which is compatible with the mode of administration selected, at least one compound of formula (I), one of the optical or geometrical isomers thereof or one of the salts thereof.
The compounds according to the invention may be administered enterally, parenterally, topically or ocularly.
Via the enteral route, the compositions may be in the form of tablets, gelatin capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or polymeric or lipid vesicles which enable controlled release. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection.
The compounds according to the invention are generally administered at a daily dose of about 0.01 mg/kg to 100 mg/kg of body weight taken in 1 to 3 doses.
Via the topical route, the pharmaceutical compositions based on compounds according to the invention are more particularly intended for the treatment of the skin and the mucosae and may be in the form of ointments, creams, milks, salves, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. They may also be in the form of microspheres or nanospheres or polymeric or lipid vesicles or polymeric patches and hydrogels which enable controlled release of the active principle. Furthermore, these topical-route compositions may either be in anhydrous form or in aqueous form, depending on the clinical indication.
Via the ocular route, they are mainly eyedrops.
These compositions for topical or ocular use contain at least one compound of formula (I) as defined above, or one of the optical or geometrical isomers thereof or alternatively one of the salts thereof, at a concentration preferably of between 0.001% and 5% by weight relative to the total weight of the composition.
The compounds of formula (I) according to the invention also find an application in the cosmetic field, in particular in body and hair hygiene and especially for treating skin types with a tendency towards acne, for promoting the regrowth of the hair, for combating hair loss, for combating the greasy appearance of the skin or the hair, in protection against the harmful effects of the sun or in the treatment of physiologically dry skin types, and for preventing and/or combating light-induced or chronological ageing.
In the cosmetic field, the compounds according to the invention can moreover be employed advantageously in combination with other compounds of retinoid-type activity, with D vitamins or derivatives thereof, with corticosteroids, with anti-free-radical agents, xcex1-hydroxy or xcex1-keto acids or derivatives thereof, or alternatively with ion-channel blockers, all of these various products being as defined above.
The present invention is thus also directed towards a cosmetic composition which is characterized in that it comprises, in a cosmetically acceptable support, at least one compound of formula (I) as defined above or one of the optical or geometrical isomers thereof or one of the salts thereof, it being possible for the said cosmetic composition to be, in particular, in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or polymeric or lipid vesicles, a soap or a shampoo.
The concentration of compound of formula (I) in the cosmetic compositions according to the invention is advantageously between 0.001% and 3% by weight relative to the entire composition.
The pharmaceutical and cosmetic compositions according to the invention can also contain inert additives or even pharmacodynamically or cosmetically active additives or combinations of these additives and, in particular: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; moisturizing agents such as glycerol, PEG-400, thiamorpholinone and derivatives thereof, or urea; anti-seborrhoea or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, the salts or derivatives thereof, or benzoyl peroxide; antibiotics such as erythromycin and esters thereof, neomycin, clindamycin and esters thereof, and tetracyclines; antifungal agents such as ketoconazole or 4,5-polymethylene-3-isothiazolidones; agents for promoting the regrowth of the hair, such as Minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide) and derivatives thereof, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) and Phenytoin (5,4-diphenylimidazolidine-2,4-dione); non-steroidal anti-inflammatory agents; carotenoids and, in particular, xcex2-carotene; anti-psoriatic agents such as anthraline and derivatives thereof and, lastly, eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid, the esters and amides thereof.
The compositions according to the invention may also contain flavour-enhancing agents, preserving agents such as para-hydroxybenzoic acid esters, stabilizing agents, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifying agents, UV-A and UV-B screening agents, and antioxidants such as xcex1-tocopherol, butylated hydroxyanisole or butylated hydroxytoluene.
Several examples for obtaining the active compounds of formula (I) according to the invention, as well as various cosmetic and pharmaceutical formulations based on such compounds, will now be given for illustrative purposes and with no limiting nature.